It has been proposed that brain disorders such as AIDS dementia complex, Alzheimers dementia, Parkinsons disease, and possibly schizophrenia are caused by progressive neurodegeneration. Oxidative stress and neuronal damage may occur when the endogenous antioxidative defense systems are severely weakened by aging, imbalanced dietary intake, and environmental or man-made neurotoxins. The objective of our research unit is to prevent brain atrophy and to improve life quality by developing neuroprotective agents and strategies against oxidative brain damage caused by free radicals. We employed both cell cultures and animal models for investigating neuroprotective and neurorescue effects of agents including antioxidants. In vitro results suggest that free radicals are unavoidable by-products of chemical reactions of oxygen, iron, and dopamine. Based on this in vitro finding we have developed a free radical-induced parkinsonian animal model for testing neuroprotective agents. In addition to manganese compounds, we discovered that iron-induced mild to moderate brain injury can be completely prevented by antioxidants such as S-nitrosoglutathione (GSNO) because it inhibits free radical generation and brain lipid peroxidation. GSNO is approximately 100 fold more potent than the endogenous antioxidant glutathione. Preliminary results also showed that GSNO protected brain neurons against damage caused by hemoglobin (i.e., stroke) and proteases (i.e., dementia). The present results indicate that free radicals and oxidative stress play a significant role in causing progressively degenerative brain disorders. The proposed neuroprotective and neurorescue effects of antioxidants can be demonstrated in cell cultures and animal models. The beneficial effects of antioxidants in degenerative brain disorders may be more visible if they were administered to patients in early preclinical stage. - neuroprotection, free radical, antioxidant, hemoglobin, iron, manganese, Parkinson's disease, dementia, oxidant stress, S- nitrosoglutathione